Cell Manufacturing on a Large Scale

Creating a kinder, gentler manufacturing process that doesn't kill the product is the goal of process developers doing large-scale cell culture for cell therapy.
Jun 02, 2008
Volume 32, Issue 6

Diane MacDonald/Getty Images
This story is about a technology so new, it hasn't been invented yet. Not quite. It's so new that "Googling" the search term "cell manufacturing" pulls up largely irrelevant entries—ones that pertain more to computer hardware configuration than to the large-scale culturing of cells. And yet it is based on traditional cell culture, one of the oldest technologies in biology and the foundation on which so many modern biological discoveries rest.

Although small-scale cell culture has been around for about a century, the notion of culturing cells on a large scale is only a decade old, invented out of the necessity to accommodate the growing commercial success of biotech-based therapeutics, mostly monoclonal antibodies and small peptide-sized molecules.


Figure 1: CompacT SelecT is a medium-throughput automated cell-culture system made by The Automation Partnership.
Protein drugs can theoretically be synthesized in a laboratory, but the procedure would be painstaking, labor intensive, and expensive. It is far more efficient to follow nature's lead and produce proteins inside the cells.

The industrial route for making protein drugs inside cells is fairly well established, even at the relatively callow age of ten. In the general paradigm, a gene for a therapeutic protein is inserted into a cell—the most popular mammalian cell for industrial purposes being a line of Chinese hamster ovary (CHO) cells. Great quantities—thousands of liters—of the genetically engineered CHO cells are cultured, fed, and nurtured and encouraged to undergo successive cell divisions to make yet more cells, which, of course, are also producing large quantities of the therapeutic protein. The therapeutic protein is secreted from the cells, or the cells are later cracked open so the therapeutic protein can be extracted and purified from them, formulated, packaged, and then sold as a drug.

Figure 2: An automated cell-culture system includes a media pump and circulation pump to push fresh medium and oxygen through the CellCube module and to eliminate spent medium. Ideally, cells within the module are exposed to uniform amounts of gases and nutrients.
Either way, the cells are disposable, used only to produce protein product before they're discarded. The techniques used to culture them are rather harsh, by cell-culture standards. "You beat the heck out of [the cells] to get the product out," says Chris Mason, an academic researcher at the Regenerative Medicine Bioprocessing Unit at University College in London. "You can treat the cells as badly as you like," he says, "just as long as they produce the bioproduct."

Treating the cells badly means that rather than allowing them to rest on a solid substrate, as most cells "prefer," cells grown for bioprocessing are suspended in a kind of nutritive broth called medium. The suspension is contained inside either a large stainless-steel vat or a large plastic (and therefore disposable) bioreactor and somehow rocked or churned or mixed to make sure that all cells have equal access to the nutrients and gases dissolved within the medium. Because they're suspended in huge vats or bags, and because they're being roiled around, the cells ball up and bump up against each other and against the vessel in which they're growing. And, as Mason noted, this harsh treatment—destructive to many cells—is fine, because the cells are not the end game. They're not the product.

lorem ipsum